Our Current Projects Project Four Australian Children of Alcoholic Female Twins This project is a continuation of work that seeks to characterize genetic and family environmental influences in the development and course of alcoholism and comorbid psychopathology, with a focus on outcomes in adolescent offspring (aged 13-21) of Australian alcoholic and control mothers and their twin sisters.  Project 4 represents a novel and rigorous investigation of critical, yet still unresolved, issues regarding the nature of alcoholism. Most importantly, we are utilizing a children-of-twins (COT) method embedded within a longitudinal design to learn more about GE correlations and interactions that characterize the environmental consequences (and genetic correlates) of maternal alcoholism, and ultimately their role in the development of alcoholism in the offspring generation. Of particular importance, this prospective study will (i) provide confirmation in a younger age-group (7-11 year-olds) of associations between parental alcoholism and offspring ADHD, ODD and CD that have emerged from our analyses of adolescents and young adults; and (ii) provide strong evidence regarding causal relations and the persistence of effects into the older adolescent and young adult years; and will help us identify young adult characteristics that qualify the impact of early stage influences and that are predictive of different alcohol use trajectories (pathways) throughout the young adult years. It is anticipated that findings will have important implications for alcoholism prevention and treatment to the extent that study findings help us identify factors (a) that are causally related to the development of alcoholism and (b) that lead to improved risk assessment, improved predictability of course, improved effectiveness in the application of intervention strategies, and improved management of the chronicity of alcoholism disorders. Project Five Molecular Epidemiology of Alcoholism and Comorbid Disorders This new MARC research project seeks to build upon gene-discovery projects such as COGA (Collaborative Study on the Genetics of Alcoholism) and similar projects which are studying treatment-ascertained alcoholics and their relatives, and the MARC-affiliated Alcohol-QTL IRPG consortium (PIs Heath, Martin, Madden, Todd), which is studying community-ascertained alcoholics and heavy smokers and their adult relatives, by incorporating a molecular genetic component into 4 mature, prospective longitudinal studies spanning the age-range from early adolescence into young adulthood, with 3-7 waves of prospective assessment. In addition to collecting DNA from the target samples (years 1-3), this research project will combine secondary data-analysis and genotyping, proceeding in 4 stages: (i) longitudinal and other phenotypic analyses to establish consistent phenotype definition across informative data-sets (not all data-sets will be informative for all phenotypes of interest) (years 1-3); (ii) behavioral genetic analyses using existing twin data sets (MOAFTS, the former MARC Project One, or other U.S. and Australian data-sets to which we have access through the MARC) to confirm heritability of phenotypes defined at stage (i), and where possible determine whether that phenotypic operationalization is optimal for understanding genetic effects (which may not be the case if the structures of genetic and environmental influences are very different) (years 1-3); (iii) genotyping for a limited number of candidate genes (years 3-5); and (iv) genetic association analysis (years 4-5). This carefully staged approach is necessary to minimize the dangers of multiple testing when combining candidate gene data and rich longitudinal data-sets. For the same reason, we focus on a limited number of candidate phenotypes where prospective data are expected to be informative for understanding the etiology of alcoholism, as justified under Background and Preliminary studies. Selection of candidate phenotypes and candidate genes is guided by the MARC focus on the roles of overlapping mechanisms of behavioral undercontrol, negative affect regulation and pharmacologic vulnerability in the etiology of alcohol use disorders (AUDs), emphasizing AUD phenotypes associated with (a) externalizing symptoms, (b) tolerance and quantitative consumption indices, (c) cognitive aspects of alcohol use (expectancies), (d) co-occurrence with tobacco dependence, and (e) negataive affect (depression, suicidality). Project Six Conjoint Alcohol and Tobacco Use: An Ecological Study The comorbidity of alcohol and tobacco use has been a central theme of ongoing MARC investigations. Existing MARC-affiliated projects have used epidemiological, behavior genetic, and laboratory methods to understand the robust associations between drinking and smoking. Previously, however, the MARC research portfolio had not included studies that bridge the basic laboratory research with the genetic epidemiology. Consequently, relatively little is known about the motivational mechanisms that contribute to the joint use of alcohol and tobacco in actual users living in their natural environments. Using Ecological Momentary Assessment (EMA; Stone & Shiffman, 1994) to investigate hypothesized mechanisms that purportedly motivate joint use of alcohol and cigarettes, we are prospectively assessing alcohol use and smoking, their subjective antecedents and sequelae, and environmental contexts in 400 smokers and 200 nonsmokers recruited from the community. Electronic diary recording, which includes morning assessments, drinking episode assessments, and smoking episode assessments, as well as random prompts, occur over a 3-week period. This design will permit within-subjects contrasts in the drinker-smokers that characterize the unique motivational sequelae of joint drinking-smoking moments relative to moments when only drinking, only smoking, or neither are taking place. Additional comparisons between drinker-smokers and drinkers only will be used to identify domains where chronic effects of smoking (e.g., chronic cross-tolerance) or other stable individual differences that differentiate smoking and nonsmoking drinkers may contribute to the pattern of motivational effects seen in drinker-smokers. Using hierarchical linear modeling, and to a lesser extent, survival analysis, unique effects of conjoint alcohol-smoking, relative to smoking alone and drinking alone, on both positive and negative affective states will be explored, and the relation between individual differences in conjoint alcohol-smoking and substance-specific changes in positive/negative affect and subsequent drinking and smoking behavior will be examined. Also, the extent to which individual difference variables (e.g., sensation-seeking; escapist motives for substance use) condition the magnitude of conjoint and substance-specific effects on alcohol and/or tobacco seeking behavior will be determined. In addition, the study will determine the association between smoking level and acute and delayed aversive (punishing) effects of alcohol, and will characterize the extent to which individual differences in these aversive consequences predict subsequent drinking behavior. Pilot Project 2 ADHD in Children of Mothers Who Smoked During Pregnancy: Does the Effect Interact with Paternal Alcoholism? In addition to the evidence for substantial genetic effects on ADHD, there is increasing evidence for the roles of parental alcoholism and maternal drinking and smoking during pregnancy in the risk of offspring ADHD. Previous studies have associated prenatal exposure to both alcohol and nicotine with increased risk of ADHD in children. Preliminary analyses also suggested (i) significant associations between parental alcoholism and ADHD, as well as between maternal smoking during pregnancy and parental alcoholism, and (ii) evidence for a genetic correlation between parental alcoholism and offspring ADHD. Given these results, in addition to genetic transmission, increased rates of maternal smoking during pregnancy associated with parental alcoholism may be an important factor contributing to the association between parental alcoholism and ADHD. Taken together, evidence suggests that both genetic and environmental risk factors for ADHD are at work in the children of alcoholics, raising the possibility that these risk factors may interact with one another. Using an innovative within-mother comparison approach, this pilot study will assess relative effects of maternal smoking during pregnancy on ADHD in 200 ‘high genetic risk’ children (100 sibling pairs with alcoholic fathers) and 200 ‘low genetic risk’ children (100 sibling pairs with no history of paternal alcoholism). The novel within-mother approach focuses on mothers who have smoked during one pregnancy but not during all pregnancies, allowing the comparison of outcomes between sibling pairs, one of which has been exposed to nicotine prenatally and the other who has not, while controlling for pertinent environmental variables (e.g., SES, parental education, etc.). Thus, the samples are chosen for environmental risk for ADHD from the maternal side (maternal smoking during pregnancy) and genetic risk for ADHD from the paternal side (those with history of DWI/alcohol problems). The sample will focus on mothers who gave birth to children between 1992-1996 (children aged 7-11). A total of 4,835 mothers who are discordant for smoking during their pregnancies have been identified from Missouri birth records. Of these, 608 have a partner (listed as the father on the child's birth record) who has been given a DWI. A total of 400 mothers will be screened for eligibility (i.e., accuracy of birth records). Those eligible to participate (200 projected) will be interviewed via telephone regarding children’s ADHD, detailed smoking during pregnancy, history of smoking and nicotine dependence, history of alcohol problems and alcohol dependence, and limited parental psychopathology (i.e., screen for ADHD, screen for CD). Pilot Project 3 Genetic Epidemiology of Alcohol and Tobacco Consumption in a Chinese Sample Alcohol and tobacco consumption are a major public health problem. Twin and family studies have suggested that both genetic and environmental risk factors are associated with both behaviors and some genetic risk factors contribute to the common risk of both behaviors. However, these results are found in respondents with European ancestry. Lack of data from Asian populations with different genetic and cultural background has limited the generalizability of these findings. We propose a feasibility twin study to examine the genetic and environmental contributions to alcohol and tobacco consumption in a Chinese population as an initial step that leads to the future large-scale replication twin study in China. We will conduct a screening interview to assess zygosity and family structure among 400 adult twins ascertained from the Qingdao Twin Registry in China and blood drawing from a randomly selected sub-sample of 82 twins and their twin siblings to confirm the accuracy of self-reported zygosity. A diagnostic interview will be administered to obtain a detail history of alcohol and tobacco smoking as well as DSM-IV alcohol and nicotine dependence, major depression, anxiety disorder and antisocial personality disorder in 200 twin pairs (50 MZ and DZ male and 50 MZ and DZ female pairs). The screening interview will be adapted from the Missouri Alcoholism Research Center (MARC) projects. The Chinese CIDI will be used to derive the DSM-IV diagnoses. The blood samples provided by the 50 of 82 twin pairs will also be used for testing candidate genes including ADH2, ALDH2, and CYP2A6 genes. The collection of twin data in this project represents an initial step that leads to establishment of a Chinese twin registry, which will allow us to conduct a large-scale cross-cultural genetic epidemiology study. This pilot project will examine the following issues for alcohol and tobacco consumption: (i) are genetic risks for alcohol or tobacco consumption and dependence lower in the Chinese twin sample than twins with European ancestry? (ii) is there evidence that alcohol and tobacco consumption and dependence share genetic risks in this Chinese twin sample as reported by other studies conducted in twins with European ancestry? (iii) is there evidence that major depression and antisocial personality disorder mediate or moderate genetic vulnerability to alcohol and tobacco consumption and dependence in this Chinese twin sample? (iv) is there evidence that ADH2, ALDH2, and CYP2A6 genes contribute to the vulnerability to alcohol and tobacco use and dependence after controlling for major depression, anxiety disorder and antisocial personality disorder?